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Protective Effects of the Nutritional Supplement Sulforaphane on Doxorubicin-Associated Cardiac Dysfunction

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ClinicalTrials.gov Identifier: NCT03934905
Recruitment Status : Not yet recruiting
First Posted : May 2, 2019
Last Update Posted : July 18, 2019
Sponsor:
Information provided by (Responsible Party):
Texas Tech University Health Sciences Center

Brief Summary:
Cardiomyopathy is a major complication of doxorubicin (DOX) chemotherapy, and 10-21% of breast cancer patients receiving DOX experience compromised cardiac function. Recent advancements, including the use of DOX with radiotherapy, have increased cancer survivorship, but it remains clinically challenging to mitigate the cardiotoxic side effects. Although there are several strategies used to reduce the occurrence and severity of DOX-induced cardiotoxicity, they are not particularly effective. Hence, there is an urgent need to develop new strategies that prevent the cardiotoxic effects of DOX but maintain its potency as a cancer therapy. Because the cellular events responsible for the antitumor activity of DOX and DOX-induced cardiotoxicity are distinctly different, it may be possible to develop therapies that selectively mitigate DOX-induced cardiotoxicity. Thus, the investigators propose to test an adjuvant therapy that combines the phytochemical sulforaphane (SFN) with DOX to attenuate DOX-induced cardiomyopathy. SFN activates the transcription factor Nrf2 and induces defense mechanisms in normal cells. Furthermore, SFN inhibits carcinogenesis and metastases and enhances cancer cell sensitivity to DOX, seemingly through Nrf2-independent mechanisms. SFN has also been tested in clinical trials of prostate cancer treatment, although never together with DOX. Our early animal studies suggest that by activating Nrf2, SFN selectively protects the mouse and rat from DOX cardiotoxicity and enhances survival. Moreover, SFN enhances the effects of DOX on cancer growth in a rat breast cancer model. The investigators suspect that SFN affects DOX metabolism in cancer cells to enhance tumor regression, or it may synergistically activate other key antitumor mechanisms. Hence, SFN may improve the clinical outcome of cancer therapy by (1) attenuating DOX cardiotoxicity and (2) enhancing the effects of cancer treatment on the tumor. Our hypothesis is that SFN protects the heart from DOX-mediated cardiac injury without altering the antitumor efficacy of DOX. In Specific Aim 1, the investigators will conduct an early-phase clinical trial to determine if SFN is safe to administer to breast cancer patients undergoing DOX chemotherapy. In Specific Aim 2, the investigators will determine if SFN decreases DOX-induced inflammatory responses and enhances Nrf2- and SIRT1-target gene expression in breast cancer patients. Notably, transcript and protein signatures in peripheral blood mononuclear cells (PBMCs) can predict cardiac function in patients undergoing DOX chemotherapy for breast cancer. In Aim 2, the investigators will determine if SFN/DOX treatment activates Nrf2- and SIRT1-dependent gene expression, alters the levels of biomarkers for presymptomatic DOX-cardiotoxicity, and mitigates the generation of cardiotoxic metabolites in PBMCs and plasma. These studies will facilitate the development of SFN co-treatment as a strategy to enhance the efficacy and safety of DOX cancer therapy.

Condition or disease Intervention/treatment Phase
Anthracycline Related Cardiotoxicity in Breast Cancer Drug: sulforaphane Drug: Placebo Oral Tablet Phase 1 Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 70 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: We plan to include 70 DOX-naïve women with breast cancer undergoing neoadjuvant chemotherapy, with no prior cardiac disease and who will receive DOX without Her-2 receptor antagonists as part of their clinical care. Potential subjects will be recruited in a randomized, controlled; double blinded pilot study comparing SFN to placebo. Study will be conducted at the TTUHSC and UMC. The trial is approved by the institutional IRB and will be registered at clinicaltrials.gov. UMC cancer center pharmacist Ajoke A. Tijani, RPh. will receive placebo and test compound from supplier and will dispense them to test subjects. Randomization will be done with assignment of a subject ID to the study subject. The list of subject IDs will be subsequently assigned to either study drug or placebo using a randomizer software.
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Official Title: Phase II Trial of Effects of the Nutritional Supplement Sulforaphane on Doxorubicin-Associated Cardiac Dysfunction (CRI18-026)
Estimated Study Start Date : October 1, 2019
Estimated Primary Completion Date : June 1, 2021
Estimated Study Completion Date : June 1, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Doxorubicin

Arm Intervention/treatment
Active Comparator: sulforaphane
Processed SFN-rich extract will be purchased in form of caplets from Nutramax Laboratories, Inc. 2208 Lakeside Blvd Edgewood, MD 21040. Caplets containing SFN-rich broccoli sprout extracts from Nutramax Labs will be dispensed to participants in sealed bottles with instructions to keep them in a household freezer. Size of the caplet will be about 2 cm in length. Dosing will be based on weight and will be dosed daily for 12 weeks.
Drug: sulforaphane
The participants will be dosed, based on weight, in a double-blind fashion with identical appearing placebo or SFN caplets in a daily dose for 12 weeks of: two caplets for individuals <100 lb., four caplets for individuals 100-200 lb. and eight caplets for individuals >200 lb. Avmacol or placebo will be prescribed by Dr. Awasthi and will be dispensed by local pharmacy or study coordinators at TTUHSC/UMC Lubbock. We will be doing pill counts to make sure that volunteers have used as directed. We will measure the Sulforaphane level in plasma by well-established method.

Placebo Comparator: Placebo
Placebo caplets will comprise of microcrystalline cellulose from Nutramax Labs and will be dispensed to participants in sealed bottles with instructions to keep them in a household freezer. Placebo pills will be identical in appearance to the sulforaphane pills and will be dosed in a similar manner (identical number of pills based on weight, daily dosing and for 12 weeks)
Drug: Placebo Oral Tablet
The participants will be dosed, based on weight, in a double-blind fashion with identical appearing placebo or SFN caplets in a daily dose for 12 weeks of: two caplets for individuals <100 lb., four caplets for individuals 100-200 lb. and eight caplets for individuals >200 lb. Avmacol or placebo will be prescribed by Dr. Awasthi and will be dispensed by local pharmacy or study coordinators at TTUHSC/UMC Lubbock. We will be doing pill counts to make sure that volunteers have used as directed. We will measure the Sulforaphane level in plasma by well-established method.




Primary Outcome Measures :
  1. Change in cardiac function after DOX therapy with or without sulforaphane through diagnostic studies [ Time Frame: At baseline and 1 year from baseline assessment. ]
    2D Echo will be used to measure cardiac function amongst patients on DOX therapy who are exposed to sulforaphane or placebo.


Secondary Outcome Measures :
  1. Elevation of troponin levels as a surrogate evidence of DOX related cardiotoxicity will be checked at baseline, prior to each DOX therapy and then at 1 year from baseline assessment (Each cycle is 14 days). [ Time Frame: At baseline, prior to each cycle of DOX, at completion of 4th cycle of DOX therapy and 1 year from baseline assessment. ]
    Troponin will be used to assess for cardiotoxicity amongst patients on DOX therapy who are exposed to sulforaphane or placebo.

  2. Tumor size in patients on DOX therapy with or without sulforaphane treatment will be assessed at baseline, at completion of DOX chemotherapy (4 cycles planned with each cycle being 14 days) and at 1 year from baseline assessment. [ Time Frame: 2 days before first DOX treatment, 2 days after completion of 4th cycle of DOX therapy and 1 year from first DOX treatment ]
    We will use PET imaging for comparison of change in tumor size for patients on DOX therapy with or without sulforaphane.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 89 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age 18 to 89 years
  2. No prior diagnosis of coronary artery, carotid artery or peripheral artery disease
  3. Not pregnant or breastfeeding (urine pregnancy test will be done if female of childbearing potential)
  4. Breast cancer requiring treatment with DOX-containing regimen above
  5. Women in child bearing age group (18-50 years) will agree to use birth control for duration of study
  6. Study subjects must be willing and able to swallow caplets, up to 8 daily.

Exclusion Criteria:

  1. Currently on a research study with an investigational drug, or has been on one in the previous 30 days
  2. Pregnant (by urine pregnancy test)
  3. Baseline ejection fraction of less than 50%, evidence of left ventricular hypertrophy or baseline EKG reported as abnormal per cardiologist.
  4. Inability to provide informed consent.
  5. Prior history of chest radiation therapy
  6. Diabetes or Hypertension or prior Myocardial infarction
  7. Trastuzumab patients
  8. Routinely taking vegetable or fruit-containing supplement pills (antioxidant phytochemicals) (daily vitamin pills ok)
  9. Inability to follow up for safety monitoring
  10. Prisoners
  11. Previous or current use of cocaine or any illicit drug
  12. Unable or unwilling to provide blood samples
  13. Taking medications known to have cardiac effects, such as but not limited to, beta blockers, anti-arrhythmic agents, non dihydropyridine calcium channel blockers, ace inhibitors, NSAIDS, diuretic agents.
  14. Unable to follow the protocol
  15. Inability to receive anthracycline due to any reason (underlying baseline cardiac dysfunction due to other reasons, with an EF under 50%)
  16. Patients already taking SFN OTC

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03934905


Contacts
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Contact: sharda p singh 8067431540 sharda.singh@ttuhsc.edu
Contact: sanjay awasthi 8067431540 sanjay.awasthi@ttuhsc.edu

Locations
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United States, Texas
Texas Tech University Health Sciences Center Active, not recruiting
Lubbock, Texas, United States, 79430
Sponsors and Collaborators
Texas Tech University Health Sciences Center
  Study Documents (Full-Text)

Documents provided by Texas Tech University Health Sciences Center:
Informed Consent Form  [PDF] January 9, 2019


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Responsible Party: Texas Tech University Health Sciences Center
ClinicalTrials.gov Identifier: NCT03934905     History of Changes
Other Study ID Numbers: L19-065
First Posted: May 2, 2019    Key Record Dates
Last Update Posted: July 18, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: All data generated from this project will be disseminated across the scientific community as rapidly as possible while adhering to the NIH Grants Policy on Availability of Research Results: Publications, Intellectual Property Rights, and Sharing Research Resources, issued in November 2016. The data will be available in password protected files, accessible only to investigators and with read only access to the databases. We will follow the guidelines established by NIH for Data Sharing Policy and Implementation and will ensure that all NIH privacy protection procedures are followed. We will make the dataset available to qualified investigators within 6 months of acceptance of the manuscript describing the main study findings. Investigators who request to use the dataset will be required to obtain IRB approval and to sign a data use agreement form before release of the data.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Time Frame: one year after completion of the study
Access Criteria: data will be provided upon request

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Texas Tech University Health Sciences Center:
doxorubicin
sulforaphane
cardiotoxicity
nrf2
heart
Additional relevant MeSH terms:
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Cardiotoxicity
Pathologic Processes
Drug-Related Side Effects and Adverse Reactions
Chemically-Induced Disorders
Radiation Injuries
Wounds and Injuries
Doxorubicin
Liposomal doxorubicin
Sulforafan
Antibiotics, Antineoplastic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anticarcinogenic Agents
Protective Agents
Physiological Effects of Drugs